All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Alzheimer's disease (AD) is a common and devastating age-dependent neurodegenerative disease. AD brain pathology is characterized by typical accumulation of proteolytic products of the amyloid precursor protein (APP), amyloid-β peptides (Aβ), which form extracellular aggregates termed Aβ plaques. These plaques are believed to contribute to disrupted cellular activities and communication in the brain, leading to neurotoxic inflammation and neuronal death [2,3]. Molecular imaging, which allows a non-invasive monitoring of pathological processes in living subjects, has the potential to enhance detection and understanding of disease and drug effectiveness. Accordingly, major efforts have been invested in developing tools to enable noninvasive detection of amyloid plaques through the skull of living AD patients and animal models [4-9]; however, noninvasive monitoring of amyloid plaques is still clinically challenging and of limited availability at high resolution [10-12]. Optical imaging constitutes a powerful, high-resolution and specific tool for in vivo imaging, as recently demonstrated using multiphoton microscopy to image Aβ plaques in vivo in the mouse brain via a cranial window [13]. The present subject matter poses an alternative and noninvasive approach in humans to image the retina of AD patients by optical modalities, provided that Aβ plaques develop in these patients' retinas and share similar properties with those in the brain.
APP is widely expressed in the retinal ganglion cells (RGCs), an outgrowth of the central nervous system (CNS), and is transported to the axonal plasma membrane and the nerve terminals via the optic nerve [14]. Formation of plaques in the retina came recently under investigation, especially in two related neurodegenerative disorders: aged-related macular degeneration (AMD) and glaucoma [50-53]. It was unclear whether Aβ-plaques are found in the retina in early or late stage of AD patients. Past evidence pointed to the presence of Aβ-plaques in retinas of glaucoma and AMD patients and their rodent models. For example, Aβ deposition in the RGC layer has been reported in glaucoma patients [50, 51]. In experimental models of glaucoma, apoptosis of RGCs has been associated with the accumulation of Aβ-peptides, and agents targeting their formation were shown to exert neuroprotective activity [52]. In AMD patients, Aβ deposits were found in drusen that correlated with the location of degenerating photoreceptors and retinal pigment epithelium cells [53].
In a Drosophila transgenic model of AD, based on the targeted expression of mutated human APP and presenilin (PS) genes, Aβ immunoreactivity was found in the compound eye, and in association with retinal photoreceptor degeneration [15]. A recent study demonstrated Aβ deposits in the retinal nerve fiber layer (NFL) and ganglion cell layer (GCL) in AD transgenic mice at an advanced stage of the disease (later than 10 months of age). The Aβ deposits were further correlated with neurodegeneration of the RGCs and with microglial activation [16].
Despite this encouraging research, there remains a need in the art for systems and methods for the diagnosis, prognosis and treatment of AD. The present subject matter meets these needs by discovering the presence of Aβ plaques in retinas of postmortem eyes of AD patients. Using mice expressing mutated forms of the human APP and PS1 genes (APPswe/PS1dE9, referred to here as AD-Tg mice), the present subject matter also provides evidence disclosing the early formation of Aβ plaques in the retina prior to their manifestation in the brain. Furthermore, the present subject matter identifies an immune-based therapy, using a weak agonist of a myelin-derived peptide loaded on dendritic cells [17, 18], effective in reducing Aβ plaques in the mouse brains and retinas of AD-Tg mice. Finally, the subject matter demonstrated that systemic injection of curcumin (diferuloylmethane), a natural compound that binds and labels Aβ plaques [19, 20], into live animals allows for non-invasive high-resolution and specific visualization of Aβ plaques in the retina. The present subject matter teaches methods that, for the first time, allow for Aβ plaques to be detected by number and location, and be repeatedly counted and monitored in real-time in the retina of AD mammals.